Whats New in Primary Malignant Musculoskeletal Tumors

Schwab, Joseph H. MD; Springfield, Dempsey S. MD; Raskin, Kevin A. MD; Mankin, Henry J. MD; Hornicek, Francis J. MD, PhD

Journal of Bone & Joint Surgery - American Volume:
doi: 10.2106/JBJS.M.01226
Specialty Update
Author Information

1Orthopaedic Oncology Service, Massachusetts General Hospital, 55 Fruit Street, Boston, MA 02114. E-mail address for J.H. Schwab: jhschwab@partners.org

Article Outline

Malignant musculoskeletal tumors are infrequent and have relatively aggressive clinical courses. Systemic spread is common in higher grade tumors, and much of the basic research reviewed herein focuses on developing new systemic therapies to help prevent and treat metastatic disease. The clinical research reviewed here focuses on outcomes after local and systemic treatment of the tumors. We have added a section of reconstructive aspects of musculoskeletal oncology, which focuses on technical and mechanical issues.

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Chondrosarcoma has no characteristic molecular alteration, and thus a target for therapy is more challenging.

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Basic Science

Work on the genetics of chondrosarcoma revealed mutations in the gene for type-II collagen (COL2A1) in 37% of the forty-nine cases studied. Further confirmation of previous reports on the presence of frequent mutations in isocitrate dehydrogenase 1 (IDH1) and IDH2 were also reported1. Another study reported the usefulness of IDH1 mutations in distinguishing chondrosarcoma from chondroblastic osteosarcoma, as the former had a mutation in IDH1 in 61% of patients whereas the latter had no mutations in IDH12.

The bone morphogenetic protein pathway is active in central chondrosarcomas and the activity-correlated grade. This is the first time that the expression of this pathway was shown to correlate with grade3. Inhibitors of this pathway are available for early clinical trials.

The transcription factor ETV5 has been linked to the regulation of matrix metalloproteinase-2 (MMP-2) in chondrosarcoma. It appears that ETV5 induces the expression of MMP-2, which degrades the surrounding matrix and thus allows chondrosarcoma cells to grow4. MMPs in cartilage tumors have been discussed as therapeutic targets for many years.

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Clinical Research

Local recurrence of chondrosarcoma continues to be a focus of interest. Lin et al. reported the rate of survival after local recurrence as well as the rate of repeat local recurrences in patients with chondrosarcoma before describing factors that influenced survival. The authors reported a ten-year survival rate of 60%, with 65% of patients experiencing more than one local recurrence. Cure is possible after local recurrence and even after more than one local recurrence; however, the authors found that several disease factors were associated with death, including metastases, higher grade, axial location, and age older than forty years. The authors confirmed previous reports that local recurrence could be associated with mortality in some patients with grade-1 chondrosarcoma, emphasizing that those tumors are a separate entity from enchondromas5. Chondrosarcomas occurring in the pelvis have been associated with worse oncologic outcomes as compared with chondrosarcomas occurring in the extremity. A retrospective study from the Rizzoli Institute reviewed 215 cases of chondrosarcoma in the pelvis but excluding the sacrum. The ten-year overall survival rate was 75%, and the tumor grade was the most important predictor of survival. Oncologic outcomes were worse in patients with periacetabular tumors than they were in patients with dedifferentiated tumors6.

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Chordomas are primary bone tumors arising in the axial skeleton from notochordal remnants.

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Basic Science

T-Brachyury is highly expressed in almost all chordomas, although its expression is not specific to chordomas. T-Brachyury is a transcription factor, and one study sought to identify the gene targets for transcription. Ninety-nine direct targets and sixty-six indirect targets were identified in a robust group of genes under the influence of T-Brachyury7. In a parallel study, the same group did a genome-wide association study of forty patients who had a diagnosis of chordoma and another 358 ancestry-matched control patients. They found a single nucleotide polymorphism in T-Brachyury that corresponded to an increased risk for the development of chordoma (odds ratio, 6.1)8. These findings were critical in the recent decision made by the National Cancer Institute to include chordoma in its therapeutic vaccine trial targeting T-Brachyury. The trial has recently completed its targeted accrual number.

In another important reported development, a chordoma animal model has been developed with use of zebra fish. This is unpublished research (personal communication from the investigator, who prefers to remain unnamed), and questions remain about the model; however, such a development would represent a major breakthrough in chordoma research.

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Clinical Research

The use of radiation to treat chordomas continues to be explored in patients who refuse surgery. When the morbidity that would be associated with surgery is deemed to be too great, radiation can be used according to the guidelines set forth in the Journal of the National Comprehensive Cancer Network9. Radiation is currently being delivered via heavy carbon ions, protons, or high-precision photons. Chordomas of the sacrum and mobile spine were treated with single-fraction stereotactic radiosurgery in a series of twenty-four patients from Memorial Sloan-Kettering Cancer Center. Seven of the twenty-four tumors were locally recurrent after surgery, and three tumors were metastatic. Seven of the twenty-four patients had stereotactic radiosurgery as neoadjuvant therapy prior to surgery, and eight had it as adjuvant therapy. Six patients had stereotactic radiosurgery delivered prior to planned surgery, but the patients refused surgery after delivery of the stereotactic radiosurgery. The authors reported their results after an average follow-up of twenty-four months, with twenty-three of twenty-four tumors remaining locally controlled according to the results of magnetic resonance imaging (MRI). Two patients developed neurologic complications, including sciatic neuropathy in one patient and vocal cord paralysis in the other10. Researchers from Massachusetts General Hospital reported the results of definitive proton radiation in twenty-four patients with chordomas in the sacrum (n = 19) and mobile spine (n = 5) who did not undergo surgery. The mean dose of radiation was 77.4 GyRBE (proton dose unit, gray relative biological effectiveness). The authors reported their results after a mean of fifty-six months of follow-up. Survival without local progression was 90.4% at three years and 79.8% at five years. The authors concluded that photon/proton-based treatment of chordoma was a good treatment option for inoperable patients11. The Paul Scherrer Institute also reported on the use of proton radiation for seven patients with chordoma, with local control rates of 80% at five years12.

The results of a phase-II trial in which the epidermal growth-factor receptor and human epidermal growth factor receptor 2 (HER2/neu) inhibitor Lapatinib was used in eighteen patients with advanced chordoma revealed progression of disease in five patients, with stable disease in seven patients and a partial response in six cases after at least six months of treatment. The authors commented that the efficacy of tyrosine kinase inhibitors might be increased in patients with chordoma if more than one inhibitor were used to help prevent escape pathways from being activated13.

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Osteosarcoma is the most common malignant primary tumor of bone.

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Basic Science

There have been no reproducible targets that have proven to be useful in patients with osteosarcoma, in part because of the heterogeneity of osteosarcomas. Alternative approaches to identifying osteosarcoma targets are now being used. Large, population-based genetic studies are now being used commonly and most recently have been used in osteosarcoma populations to explore potential links to genetic aberrations and the development of cancer. A recent study found two loci of interest by performing genome-wide association studies comparing 941 patients with osteosarcoma to 3291 without osteosarcoma. The loci were found on the short limb of chromosome 6 and 2, respectively, with the GRM4 gene (encoding for metabotropic glutamate receptor 4) found within the region on chromosome 6. The authors advocated further investigation of these regions of DNA14.

One of the few consistently reported genes thought to play an important role in osteosarcoma is the tumor suppressor protein 53 (p53), which has long been associated with osteosarcoma. Similarly, runt-related transcription factor 2 (RUNX2) is an important regulator of osteoblasts and has been associated with osteosarcoma when RUNX2 becomes dysregulated. A recent study provided insight into the important interaction between these two genes. RUNX2 is a suppressor of osteoblast proliferation, and it tends to maintain cells in a quiescent differentiated state. This is somehow paradoxical, as its overexpression has been associated with osteosarcoma. The authors showed that absent or suppressed p53 function leads to decreased microRNA miR-34c, which normally downregulates RUNX2. Since mir-34c is absent, RUNX2 activity increases. The study showed that RUNX2 inhibits p21 activity, which leads to increased cell proliferation. The study emphasizes the complex relationship found in cancer mechanics, whereby the kinetics of inhibition or stimulation are as important as the signal that they send. It also demonstrates a key link between the well-known bone regulatory gene RUNX2 and the well-known osteosarcoma-associated tumor suppressor p5315.

Researchers discovered the potential importance of CD44 in osteosarcoma. CD44 is a transmembrane glycoprotein that is important in cell-cell interactions, cellular adhesion, and migration. The researchers designed a study whereby CD44 was silenced with use of small hairpin RNA (shRNA), which led to an enhanced malignant phenotype. Knockdown of CD44 led to increased pulmonary metastases in their mouse model16.

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Clinical Research

The use of serum biomarkers in osteosarcoma has several potential roles. First, as a means to predict survival, biomarkers can help inform and guide clinicians and patients in their choice of treatment. Second, a biomarker can be used to stratify patients in clinical trials, with an ideal biomarker accurately predicting whether patients are at high or low risk. Third, biomarkers can serve as a means of assessing treatment effects. The report by Nakamura et al. therefore proves quite interesting, as the authors found C-reactive protein to predict poorer disease-specific survival at five years (57% versus 79%). This result confirms those reported by other investigators of osteosarcoma and is similar to what has been reported by investigators of soft-tissue sarcoma. The use of C-reactive protein in these patients certainly warrants consideration, whether it is used for research purposes or in clinical care17.

The rationale for the use of neoadjuvant chemotherapy in patients with osteosarcoma was outlined well in the study by Jones et al.18. The rationale was that neoadjuvant chemotherapy allowed surgeons to perform less aggressive surgery after chemotherapy was delivered because there was an anticipated response that would allow the sparing of important anatomic structures. The authors pointed out that this rationale, while long held, is not based on data. So they sought to explore whether neoadjuvant chemotherapy did indeed allow a less aggressive surgical plan. The authors reviewed MRI results before and after chemotherapy treatment and asked reviewers to provide a surgical plan based on the images but blinded to the timing of the images. The authors found that their review of the images actually led to a more aggressive surgical plan after neoadjuvant chemotherapy was delivered as compared with the plan that they provided before chemotherapy was delivered. Although this was a small, retrospective study, it was well conceived. The results provide the impetus for further study and remind us to question our strongly held beliefs, particularly when they are not supported with strong data18.

Abdel et al. reported on 112 malignant tumors in the proximal part of the fibula, with osteosarcoma being the most common subtypen19. The report specifically looked at issues pertaining to the anatomy of the region, with an emphasis on the rate of peroneal nerve palsy as well as instability of the lateral side of the knee after surgery. Instability was not an issue, and the authors attributed this result to their technique of resection and reconstruction of the lateral collateral ligament and biceps tendon. In addition, peroneal nerve palsy occurred in only 2% of cases. Clinical studies are employing the Surveillance, Epidemiology, and End Results (SEER) database as well as meta-analyses to assess risk factors and to better predict outcomes. In a recent study, the SEER database was used to assess independent risk factors for presenting with metastatic osteosarcoma. Several factors were found to be important, including age over sixty years and tumor location in the axial skeleton20. The size of the tumor was also important, as each centimeter increase in size carried a 10% increased risk of metastases. Patients who were from a lower socioeconomic strata were also more likely to present with metastases21. These data are corroborated by a separate study that evaluated socioeconomic-related outcomes in patients with osteosarcoma22. The same group reported on the concept of conditional survival in patients with osteosarcoma and Ewing sarcoma23. Using the SEER database, they reported that if a patient with localized osteosarcoma lived for five years without a relapse, then, statistically speaking, that patient had a better chance of living another five years (91%) than what would have been predicted after the initial diagnosis (75%). In other words, the longer that a patient lives with osteosarcoma, the less likelihood there is that he or she will have a relapse. They found similar results in patients with Ewing sarcoma. Patients who presented with metastatic osteosarcoma had a five-year survival of 36%, whereas patients who were five-year survivors of metastatic osteosarcoma had an improved likelihood of 85% to survive another five years23. Researchers from St. Jude Children’s Research Hospital analyzed factors associated with improved survival after a first relapse in patients with osteosarcoma. If the relapse occurred eighteen months after the first osteosarcoma was diagnosed, and if the relapse was treated surgically, then patients had better survival. Patients with recurrence in both lung fields had a poor prognosis24. A meta-analysis of prospective studies utilizing neoadjuvant chemotherapy in osteosarcoma demonstrated improved survival for younger patients. The authors also found a significant survival benefit with female sex, perhaps because of a fundamental difference in the way that men and women react to chemotherapy25. This finding is corroborated by the results of a separate study from Singapore, in which female sex had a positive impact on survival26. The protein Ezrin continues to garner interest as a marker in osteosarcoma. It is important in cell-matrix and cell-cell interaction, and a meta-analysis of 318 cases revealed that Ezrin expression, as measured by immunohistochemistry, correlated with a higher risk of recurrence and a worse overall survival rate for patients with osteosarcoma27.

A recent statement paper from the leadership of the Children’s Oncology Group outlined a road map of targets whereby clinical trials are forthcoming. The trials included the targeting of RANKL and GD2 and were meant to include patients who had a relapse after conventional chemotherapy treatment. RANKL has received much interest for its role in preventing pathologic fractures as well as for its efficacy in managing giant cell tumors. It is expressed in osteosarcoma, and preclinical models offer hope that it will be effective in patients. GD2 is a glycosphingolipid that is normally expressed on melanocytes and peripheral nerves as well as in the central nervous system, and it is known to be expressed in over 90% of osteosarcomas. A phase-I study of the drug included two patients with relapsed osteosarcoma; both patients had complete responses to the drug, and the response was durable for eight months. Patients with relapsed osteosarcoma will also be included in forthcoming phase-II trials that will make use of a pan-tyrosine kinase inhibitor, a specific insulin-like growth factor 1 receptor (IGF1R) inhibitor, and a mammalian target of rapamycin (mTOR) inhibitor28.

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Ewing Sarcoma

Ewing sarcoma has the characteristic 11;22 translocation resulting in a protein product that can be targeted for treatment. The other common primary malignant tumors of bone lack a characteristic translocation.

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Basic Science

Tumor micro-environment continues to garner interest as researchers explore the impact that local factors have on tumor growth. An interesting study in which Ewing sarcoma cells were used demonstrated that cells grown in their three-dimensional culture model were much less sensitive to chemotherapy than the same cells grown in a monolayer. This study emphasized the need to design pre-animal studies with the tumor micro-environment in mind29.

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Clinical Research

In a large series of adult Ewing sarcoma patients from the Mayo Clinic, outcomes were analyzed for 102 patients. The authors reported improved results in the modern portion of their study (1993 through 2007 versus 1977 through 1992) reflecting a move toward using surgery along with etoposide and ifosfamide-based chemotherapy. The authors reported a five-year overall survival rate of 73% and a five-year event-free survival rate of 60% in their modern group. Further, local failure was 18% in the surgery group, compared with 33% in the radiation group and 0% with the combination of the two local modalities30.

The Children’s Oncology Group recently completed a trial that analyzed the impact of decreasing the interval between doses of chemotherapy with use of the drugs vincristine, doxorubicin, cyclophosphamide, ifosfamide, and etoposide. The trial revealed that decreasing the interval between doses to two weeks from three weeks improved survival without causing undue toxicity31.

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Osseous Reconstructive Surgery

Following extensive metastatic disease or surgical resection of primary malignant tumors of bone, reconstruction of the defect can be challenging. The following section discusses clinical research related to issues associated with stem length, stem fixation, and expandable prostheses as well as recent research on the use of navigation in musculoskeletal oncology.

Xing et al. evaluated the utility of a long-stem endoprosthesis in treating metastatic disease of the proximal part of the femur. The authors point out the long-held teaching that long stems help mitigate the risks associated with local tumor progression and progression in the distal aspect of the femur. Two hundred and six cases were reviewed and stratified on the basis of the length of the stem that was used. Local progression of disease and the occurrence of new distal femoral lesions were rare (n = 11 and n = 6, respectively); however, acute cardiopulmonary complications were more frequent in the long-stem group (18%) than they were in the short-stem group (7.5%). The study called into question the routine use of a long-stem prosthesis32.

Fixation of an endoprosthesis to bone can prove challenging after tumor resection. The Compress system was designed to take advantage of Wolff’s law, stimulating bone growth via compression rather than stimulating osteolysis by shielding the bone from stress. The implant survivorship for eighty-two patients who underwent implantation of the Compress prosthesis (Biomet, Warsaw, Indiana) was reported after a median follow-up of forty-three months. Five-year and ten-year prosthetic survival was 85% and 80%, respectively, with failures attributed to necrosis and or fracture as well as poor compliance by patients. The results provide a strong rationale for considering this type of fixation, as the failure rate compared favorably to historical controls33.

Conventional stems have traditionally been fixed with methylmethacrylate; however, uncemented stems continue to gain acceptance in limb-salvage surgery. In a retrospective study of 232 patients from 2002 through 2007 comparing cemented to cementless stems for limb salvage, Pala et al. found that cementless stems had a better overall survival and better infection-free survival than cemented stems had34. Expandable prostheses continue to undergo scrutiny, and a study from the Rizzoli Institute evaluated thirty-two cases in which either the Kotz prosthesis or the Repiphysis was utilized. The authors reported a mean lengthening of 28 mm, and six of nine patients who reached skeletal maturity had limb-length inequality. Although expansion of the Kotz prosthesis requires surgery, that prosthesis had better implant survival than the less invasive Repiphysis. The overall implant-related complication rate was 51%35.

Computer navigation continues to gain acceptance in orthopaedic oncology. The use of three-dimensional models is proving more feasible as the software development continues to improve. One report of twenty-eight cases (involving the femur in seventeen, the pelvis in six, the sacrum in two, the tibia in two, and the humerus in one) documented the difference between planned osteotomies and actual osteotomies with use of three-dimensional image-guided methods, with the overall difference and standard deviation being 2.5 mm ± 2.3 mm36. Other image-guided techniques have utilized custom jigs based on computed tomographic images37. Still others have relied on robotics, which further improved the accuracy of the osseous cuts38. It is clear that navigation will play a larger role in orthopaedic oncology as software and imaging techniques develop.

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Soft-Tissue Sarcoma

Unlike the management of bone sarcomas, the management of soft-tissue sarcoma is more controversial in terms of adjuvant therapy and its implications.

A phase-II trial evaluating the use of preoperative image-guided, intensity-modulated radiation therapy (IG-IMRT) and its relationship to wound complications was reported. Eighteen (30.5%) wound complications occurred in fifty-nine patients. The results were compared with a previous trial from the National Cancer Institute of Canada, and there was no significant difference in the overall wound complication rate (30.5% versus 43%); however, the need for soft-tissue transfer was significantly lower in the IG-IMRT group. Further studies are needed, but there appears to be some advantage to using IG-IMRT in terms of mitigating the need for soft-tissue flaps39.

Researchers from Mayo Clinic Scottsdale evaluated their cases of soft-tissue sarcoma that required unplanned further surgery for local or free tissue transfer to manage a nonhealing wound. They identified seventy-nine patients who were treated with surgery and radiation during the period of 1997 through 2010 who met their inclusion criteria. They included patients who had either preoperative or postoperative radiation, and they did not find a difference in the rate of flap usage in patients who were treated with preoperative radiation as compared with patients who were treated with postoperative radiation. They found that lower-extremity location as well as neurovascular involvement were risk factors for the development of a nonhealing wound that required additional surgery40.

In a retrospective review, Gladdy et al. reported on 353 cases of leiomyosarcoma, including leiomyosarcomas in abdominal and/or retroperitoneal locations as well as in the extremities41. The two most important predictors of disease-specific survival were tumor grade and size. The authors reported local failure rates of 51% in the abdominal-retroperitoneal group and 33% in the extremity. Risk factors for local failure were tumor size and surgical margin41. In another report from Memorial Sloan-Kettering Cancer Center, the authors sought to demonstrate that Bayesian methodology could be used to illustrate complex hierarchical relationships between prognostic features in localized soft-tissue sarcoma. They included 1318 patients who had complete (R0) resections and subjected them to Bayesian belief network modeling and found that Bayesian belief network modeling recapitulated what had previously been found with use of more conventional statistical analyses, lending credence to the idea that Bayesian belief network modeling may be a viable means by which to assess outcomes in patients who have soft-tissue sarcoma42. Cahlon et al. added another postoperative nomogram to assess the risk of local recurrence after limb-sparing surgery without adjuvant radiation. Factors included in the nomogram were age (fifty years or younger, or older than fifty years), size (5 cm or less, or longer than 5 cm), margin status (positive or negative), grade (low or high), and histology subtype, which provided a concordance index (CI) of 0.73, with a CI of 0.5 equal to a coin toss and a CI of 1.0 indicating perfect discrimination43.

Another study challenged the use of traditional prognostic parameters, including grade, tumor size, and depth, when weighing the risks of local recurrence for soft-tissue sarcoma. The authors argued that these parameters were highly associated with the development of metastases and subsequent death. Most authors have assessed the risk of local recurrence using Kaplan-Meier methodology, which has a flaw when the outcomes being assessed are in competition with one another. For instance, if patients die they will be censored, but they will still be considered to be at risk for local recurrence with use of Kaplan-Meier methods. Local recurrence and death are competing variables, and so Kaplan-Meier methods should not be used in this instance. The authors conclude that local treatment should not be based on grade, size, or depth but rather on surgical margins and presentation status (primary or recurrent), as these parameters will best guide the risk assessment for local failure44.

The Radiation Therapy Oncology Group reached a consensus on how to manage peritumoral edema surrounding soft-tissue sarcomas. The issue stems from wanting to include edema that potentially harbors tumor cells in the clinical target volume of radiation but not radiating tissue that did not actually represent edema. The Radiation Therapy Oncology Group sought to assess how well radiation oncologists agreed in deciding which areas to radiate. The authors reported a kappa value of 0.71 (substantial agreement) with regard to which areas of edema should be included in the clinical target volume45.

The combination of chemotherapy (mesna, adriamycin, ifosfamide, and dacarbazine) with preoperative radiation followed by surgery plus or minus postoperative radiation mitigates the risk of local recurrence in high-risk patients (large tumor size and high grade). A recent retrospective report of sixty-six patients revealed a local failure rate of six (9%) and distant failure in twenty (30%) with use of this regimen, with a five-year overall and disease-specific survival of 86% and 89%, respectively46.

Specialty Update has been developed in collaboration with the Board of Specialty Societies (BOS) of the American Academy of Orthopaedic Surgeons.

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Disclosure: One or more of the authors received payments or services, either directly or indirectly (i.e., via his or her institution), from a third party in support of an aspect of this work. In addition, one or more of the authors, or his or her institution, has had a financial relationship, in the thirty-six months prior to submission of this work, with an entity in the biomedical arena that could be perceived to influence or have the potential to influence what is written in this work. No author has had any other relationships, or has engaged in any other activities, that could be perceived to influence or have the potential to influence what is written in this work. The complete Disclosures of Potential Conflicts of Interest submitted by authors are always provided with the online version of the article.

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